Alcoholism is a complex disease influenced by polygenetic and polyenviromnental factors. The identification of the genes that affect risk for alcoholism is a daunting task due to genetic heterogeneity within the human population. Inbred mouse strains serve as useful model organisms to study traits related to alcoholism such as ethanol dependence (withdrawal). The C57BL/6J (B6) and DBA/2J (D2) inbred strains represent the most extensively used animal models for testing hypotheses related to ethanol-associated phenotypes. High resolution mapping for quantitative trait loci (QTL) and candidate gene analyses has identified Mpdz as a compelling candidate gene affecting risk for acute ethanol withdrawal in B6 and D2 mice and mice derived from crosses between these progenitors. Mpdz encodes a multiple PDZ domain protein and is highly polymorphic within our mapping populations. We have developed a congenic strain, D2.B6-Mpdz, that posses a 0.9 centimorgan (cM) region containing Mpdz from the B6 strain, introgressed on the background D2 strain. ne D2.B6-Mpdz congenic strain shows less severe acute ethanol withdrawal compared to the D2 background strain. In this proposal we focus on the hypothesis that genetic differences in acute ethanol withdrawal severity are due to, at least in part, genetic variation in Mpdz resulting in alterations in, co-localization and interaction, behavioral sensitivity to, and functional coupling with 5-HT2A, 5-HT2B, and/or 5-HT2C receptor subtypes. These studies will be important for generating future hypothesis about the role of Mpdz in the genetics of ethanol dependence.